This proposal is a continuation of our grant to delineate the genetics of Alzheimer disease [AD], the most common form of dementia after age 40. Within the past five years, four AD genes have been described. APP, PS-I and II are autosomal dominant causative loci in early (<60) familial AD but represent <2% of all AD cases. The vast majority of cases are late- onset familial or sporadic AD. Through the present grant, the laboratories of Drs. Pericak-Vance and Haines were the first to describe the increased risk related to the APOE-4 allele and the protective effect of the APOE-2 allele. By all estimations, APOE accounts for approximately 50% of the total predicted genetic effect and is the single most important biological risk factor yet identified in AD. Although this finding has dramatically changed the focus of AD research, another 50% of genetic etiology of AD remains unexplained. In addition to delineating the APOE effect, we have completed a genome screen using our initial set of extended late-onset pedigrees and have identified several regions deserving more scrutiny. We have now expanded our data set from 52 to 200+ multiplex late-onset AD families (250+ sampled affected sibpairs) and have 500+ sporadic AD patients and 300+ spouse controls. We also have identified the genetically isolated Indiana Amish population who, despite having a lower prevalence of AD and a decreased frequency of APOE-4, maintain familial aggregation. The above resources permit a more detailed and sophisticated genome screening and analyses to identify all major and moderate genetic effects in AD, something not possible even three years ago. We will use newly described sibpair and affected- relative-pair analyses in conjunction with lod score analysis to make greatest use of the screening data. We will also examine gene/gene interactions between the regions we (or others) conform as harboring AD genes. The ultimate goal of our proposal is the identification of all major loci involved in AD, the first step in combating this devastating neurodegenerative disease.